TW202421127A - 5H-pyrrolo[2,3-D]pyrimidin-6(7H)-one and crystal of salt thereof - Google Patents

Abstract

Provided is a type-I crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one that has, in a powder X-ray diffraction spectrum (CuK[alpha]), peaks at least two diffraction angles (2[Theta] ± 0.2 DEG) selected from the following (a) and at least two diffraction angles (2[Theta] ± 0.2 DEG) selected from the following (b). (a) 6.2 DEG, 9.3 DEG, 9.7 DEG, 11.1 DEG, 15.4 DEG, and 25.1 DEG (b) 6.7 DEG, 8.3 DEG, 8.7 DEG, 13.0 DEG, 13.7 DEG, 16.3 DEG, 16.9 DEG, 17.7 DEG, 18.7 DEG, 19.4 DEG, 20.3 DEG, 25.9 DEG, and 26.5 DEG.

Description

Crystallization of 5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one and its salts

The present invention relates to a crystal of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one and a salt thereof, which has excellent storage stability and hygroscopicity and can be used as a medicine or a raw material for a medicine, and a pharmaceutical composition containing the crystal.

Generally speaking, when a compound is used as an effective active ingredient of a pharmaceutical product, chemical and physical stability of the compound is necessary in order to stably maintain quality and/or facilitate storage management.

Patent Document 1 describes 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (hereinafter also referred to as "Compound (I)") represented by the following formula (I) as a compound having excellent inhibitory activity against at least one member selected from the group consisting of Akt, Rsk and S6K and/or a cancer cell proliferation inhibitory effect, and/or as a medically useful compound for treating various diseases (especially cancer) in which at least one member selected from the group consisting of Akt, Rsk and S6K is involved.

[Chemistry 1] (I) However, Patent Document 1 does not describe the crystal form of the compound, and the stable crystal form of Compound (I) and its preparation method are still unknown. [Prior Art Document] [Patent Document]

Patent document 1: International Publication No. 2017/200087

[The problem the invention is trying to solve]

The purpose of the present invention is to provide a crystal of a free form of compound (I) and a crystal of a salt thereof that can be used as a pharmaceutical or a pharmaceutical raw material. [Technical means for solving the problem]

In order to solve the above problem, intensive research was conducted, and as a result, three crystal forms (I-type crystal, II-type crystal, and III-type crystal) were found as free forms of compound (I). Furthermore, crystals of the hydrochloride salt and the maleic acid salt of compound (I) were found. It was found that these crystals have excellent solid stability and/or low hygroscopicity.

That is, the present invention provides the following [1] to [32]. [1] A type I crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in a powder X-ray diffraction spectrum (CuKα). (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5° [2] The I-type crystal of the free body described in [1] has peaks at at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in its powder X-ray diffraction spectrum (CuKα). (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5° [3] The I-type crystals of the free body described in [1] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5° [4] The I-type crystal of the free body described in [1] has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in Figure 1. [5] The I-type crystal of the free body described in [1] has an endothermic peak with a peak temperature of about 235°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [6] A pharmaceutical composition comprising a form I crystal of the free form described in any one of [1] to [5]. [7] A method for producing a form I crystal of the free form described in [1], comprising: dissolving 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one in a solution thereof; a step of dissolving the obtained product in a solvent 1, and adding a solvent 2 to the obtained solution to obtain 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one. [8] The method described in [7], wherein the solvent 1 is dimethyl sulfoxide and the solvent 2 is water, or the solvent 1 is tetrahydrofuran and the solvent 2 is n-heptane, ethyl acetate or 2-propanol. [9] The method described in [7], wherein the solvent 1 is dimethyl sulfoxide and the solvent 2 is water. [10] The I-type crystals of the free form described in [1] are obtained by crystallizing 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidine-6( 7H)-one was dissolved in dimethyl sulfoxide, and water was added to the obtained solution to obtain 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one. [11] A form II crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in its powder X-ray diffraction spectrum (CuKα). (a) 10.4°, 22.9° and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8° and 26.5° [12] The form II crystal of the free body described in [11] has peaks at at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα). (a) 10.4°, 22.9° and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8° and 26.5° [13] The II-type crystals of the free body described in [11] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5° and 27.9° [14] The form II crystal of the free body described in [11] has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG3. [15] The form II crystal of the free body described in [11] has an endothermic peak with a peak temperature of about 234°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [16] A pharmaceutical composition comprising a form II crystal of the free form described in any one of [11] to [15]. [17] A form III crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in its powder X-ray diffraction spectrum (CuKα). (a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7° [18] The III-type crystals of the free body described in [17] have peaks at three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα). (a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7° [19] The III-type crystals of the free body described in [17] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2° and 26.7° [20] The III-type crystal of the free body described in [17] has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in Figure 5. [21] The III-type crystal of the free body described in [17] has an endothermic peak with a peak temperature of about 234°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [22] A pharmaceutical composition comprising a III-form crystal of the free form described in any one of [17] to [21]. [23] A crystal of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one hydrochloride, which has peaks at at least three diffraction angles selected from the following diffraction angles (2θ±0.2°) in its powder X-ray diffraction spectrum (CuKα). 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0° and 31.6° [24] The crystals of the hydrochloride salt described in [23] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0° and 31.6° [25] The crystals of the hydrochloride described in [23] have a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG7. [26] The crystals of the hydrochloride described in [23] have an endothermic peak with a peak temperature of about 241°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [27] A pharmaceutical composition comprising a crystal of the hydrochloride salt as described in any one of [23] to [26]. [28] A crystal of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one cis-butenedioic acid salt, which has peaks at at least three diffraction angles selected from the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7° and 30.8° [29] The crystals of maleic acid salt as described in [28] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7° and 30.8° [30] The crystals of maleic acid salt as described in [28] have a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG9. [31] The crystals of the maleic acid salt as described in [28] have an endothermic peak with a peak temperature of about 245°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [32] A pharmaceutical composition comprising the crystals of the maleic acid salt as described in any one of [28] to [31].

Furthermore, the present invention provides the following [33] to [60]. [33] A method for treating a tumor, comprising the step of administering the pharmaceutical composition described in [6] to a subject. [34] A method for treating a tumor, comprising the step of administering the pharmaceutical composition described in [16] to a subject. [35] A method for treating a tumor, comprising the step of administering the pharmaceutical composition described in [22] to a subject. [36] A method for treating a tumor, comprising the step of administering the pharmaceutical composition described in [27] to a subject. [37] A method for treating a tumor, comprising the step of administering the pharmaceutical composition described in [32] to a subject. [38] A type I crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for the treatment of tumors, wherein the crystal has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα). (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5° [39] The I-type crystal of the free body described in [38] has peaks at at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in its powder X-ray diffraction spectrum (CuKα). (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5° [40] The I-type crystals of the free body described in [38] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5° [41] The I-type crystal of the free body described in [38] has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in Figure 1. [42] The I-type crystal of the free body described in [38] has an endothermic peak with a peak temperature of about 235°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [43] A II-form crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for use in the treatment of tumors, wherein the crystal has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα). (a) 10.4°, 22.9° and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8° and 26.5° [44] The form II crystal of the free body described in [43] has peaks at at least 4 diffraction angles (2θ±0.2°) selected from the following (b). (a) 10.4°, 22.9° and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8° and 26.5° [45] The form II crystals of the free body described in [43] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5° and 27.9° [46] The form II crystal of the free body described in [43] has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in Figure 3. [47] The form II crystal of the free body described in [43] has an endothermic peak with a peak temperature of about 234°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [48] A III-form crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for use in the treatment of tumors, wherein the crystal has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα). (a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7° [49] The III-type crystal of the free body as described in [48] has peaks at at least 4 diffraction angles (2θ±0.2°) selected from the following (b). (a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7° [50] The III-type crystals of the free body described in [48] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2° and 26.7° [51] The III-type crystal of the free body described in [48] has a powder X-ray diffraction spectrum (CuKα) substantially the same as that shown in FIG5. [52] The III-type crystal of the free body described in [48] has an endothermic peak with a peak temperature of about 234°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [53] A crystal of the hydrochloride of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for use in the treatment of tumors, wherein the crystal has peaks at at least three diffraction angles selected from the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0° and 31.6° [54] The crystals of the hydrochloride salt described in [52] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0° and 31.6° [55] The crystals of the hydrochloride salt described in [53] have a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG7. [56] The crystals of the hydrochloride salt described in [53] have an endothermic peak with a peak temperature of about 241°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [57] A crystal of the maleic acid salt of the free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for the treatment of tumors, wherein the crystal has peaks at at least three diffraction angles selected from the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7° and 30.8° [58] The crystals of maleic acid salt as described in [57] have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα). 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7° and 30.8° [59] The crystals of maleic acid salt as described in [57] are crystals having a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG9. [60] The crystals of maleic acid salt described in [57] have an endothermic peak with a peak temperature of about 245°C in thermogravimetric-differential thermal analysis (TG-DTA analysis). [Effects of the invention]

According to the present invention, a stable crystalline form of the above-mentioned compound (I) is provided, which can be used as a compound having an antitumor effect. In addition, the stable crystalline form of the compound (I) of the present invention and the method for preparing the same are not known at present. In the present invention, the crystalline form of the free form of the compound (I) (form I crystal, form II crystal, form III crystal), the crystal of the hydrochloride salt, and the crystal of the maleic acid salt are superior to other crystalline forms in terms of low hygroscopicity and/or solid stability, and therefore are useful forms when the compound is used as a pharmaceutical raw material.

In the present specification, when simply described as "Compound (I)", it means 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, and is used to include the meaning of "amorphous form" or "crystalline".

In the salt of compound (I), the molar equivalent of the acid relative to compound (I) can be analyzed, for example, by NMR (Nuclear Magnetic Resonance) or liquid chromatography. In the present invention, when the crystallization of the hydrochloride, maleic acid or acetate of compound (I) is recorded, the molar ratio of compound (I) to hydrochloric acid, maleic acid or acetic acid is 1:1, which can be determined by analysis such as ¹ H-NMR. Generally, in the salt of an organic compound, the molar ratio of the acid to the organic compound can be determined by comparing the integral value of the protons of the methyl group of the acid with the integral value of at least one proton of the organic compound. It is known that the integral value of protons will produce errors due to corrections such as the baseline of the ¹ H-NMR graph, so the molar ratio of acid to organic compound in the range of 0.8 to 1.2:1 can be regarded as 1:1.

Compound (I) can be synthesized according to the method described in, for example, International Publication No. 2017/200087 (for example, the method described in Example 32 of the publication), but is not limited to the method.

As used herein and unless otherwise specified, the term "crystalline" and related terms used herein mean that when used to describe a compound, substance, modification, material, ingredient, or product, it is substantially crystalline when the compound, substance, modification, material, ingredient, or product is determined by X-ray diffraction. For example, see Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); U.S. Pharmacopoeia, 23rd edition, 1843-1844 (1995). "Crystal" also includes hydrates or solvates (pseudopolymorphs), co-crystals. In this specification, the terms "crystal" and "crystalline form" can be used interchangeably.

In the art, the following is known: even in a multi-component system that can form a salt (accompanied by proton transfer caused by acid-base reaction), the main component (drug substance) and the auxiliary components (coformer, counter ion, solvent) form a complex through weak intermolecular interactions such as hydrogen bonds or other interactions (e.g., Cryst. Growth Des. 2012, 12, 2147-2152 dx.doi.org/10.1021/cg3002948). The "crystal" of the "salt" in the present invention also includes the crystallization of such a multi-component complex ("eutectic").

As used herein and unless otherwise indicated, the terms "amorphous", "amorphous form", and related terms used herein mean that the substance, component, or product is not substantially crystalline as determined by X-ray diffraction. In particular, the term "amorphous form" describes an irregular solid form, i.e., a solid form lacking crystalline order over long distances.

The term "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable salts are safe for ingestion by animals or humans.

The technique used to characterize the crystalline and amorphous forms is not limited, and can be thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibration spectroscopy such as infrared (IR) and Raman spectroscopy, solid nuclear magnetic resonance (NMR) spectroscopy, optical microscope observation, high temperature stage optical microscope observation, scanning electron microscope observation (SEM), electron beam crystallography and quantitative analysis, solubility measurement, and other well-known techniques in the field of technology. The characteristic unit lattice parameter is not limited, and can be determined using one or more techniques such as X-ray diffraction represented by single crystal diffraction and powder diffraction and neutron diffraction. As a technique useful for analyzing powder diffraction data, profile refinement such as Ritterwald refinement can be cited, which can be used, for example, to analyze diffraction peaks associated with a single phase in a sample containing two or more solid phases. As another method useful for analyzing powder diffraction data, unit lattice indexation can be cited, which allows the industry to determine the unit lattice parameters from a sample containing crystalline powder.

Furthermore, due to the nature of the data, the diffraction angles of the powder X-ray diffraction pattern as well as the overall pattern are important in determining the identity of the crystal. The relative intensity of the powder X-ray diffraction pattern may vary depending on the direction of crystal growth, particle size, and measurement conditions, and should not be interpreted strictly.

Crystals can be identified by peaks in the powder X-ray diffraction pattern. Here, the "peak" is selected as a peak having an intensity of 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 15% or more, or 20% or more of the maximum peak among the intensity peaks obtained by the powder X-ray diffraction spectrum (CuKα). Select a peak having an intensity of 5% or more of the maximum peak among the obtained intensity peaks, more preferably 6% or more of the maximum peak among the obtained intensity peaks, more preferably 7% or more of the maximum peak among the obtained intensity peaks, more preferably 8% or more of the maximum peak among the obtained intensity peaks, more preferably 9% or more of the maximum peak among the obtained intensity peaks, more preferably 10% or more of the maximum peak among the obtained intensity peaks, further preferably 15% or more of the maximum peak among the obtained intensity peaks, and particularly preferably 20% or more of the maximum peak among the obtained intensity peaks.

The values obtained from various patterns may sometimes have slight errors due to the direction of crystal growth, particle size, measurement conditions, etc. Therefore, in this specification, the values of the diffraction angle (2θ) in the powder X-ray diffraction pattern may have a measurement error within the range of about ±0.2°.

In addition, the endothermic peak in the thermogravimetric-differential thermal analysis (TG-DTA) curve may vary in measurement temperature due to the temperature rise per minute, sample purity, etc. In this specification, the term "near" in the TG-DTA measurement temperature value means a temperature value within ±2, 3, 4 or 5°C of the value. The temperature range is preferably ±5°C, more preferably ±4°C, further preferably ±3°C, and most preferably ±2°C.

In one embodiment, the crystalline form of compound (I) disclosed in this specification may include multiple crystals (polymorphs) with spatially regular atomic arrangements, and may produce different physicochemical properties. In one embodiment, the crystalline form disclosed in this specification may be a mixture containing polymorphs.

The crystalline form of the compound (I) of the present invention is sometimes characterized by a combination of the embodiments described below, which are not mutually exclusive. For example, the crystalline form of the compound (I) is sometimes characterized by a combination of the above peaks of the X-ray diffraction pattern and the above endothermic peaks measured by TG-DTA.

Compounds labeled with isotopes (e.g., deuterium, 3H, 14C, 35S, 125I, etc.) also include the compounds described in this specification or their pharmaceutically acceptable salts.

The crystalline forms of some of the compounds (I) disclosed in this specification are stable when exposed to conditions of about 25, 30, 35, 40, 45, 50, 55, 60, 65 or 70°C and about 65, 70, 75, 80 or 85% relative humidity for about 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, or 156 weeks or more and about 160, 156, 150, 138, 126, 114, 102, 90, 78, 66, 54, 42, 30, 24, 18, 12 or 6 weeks or less. The conditions may be closed conditions or open conditions. When used in this manual, the "closed" condition means the condition in which the lid of the bottle containing the sample is closed or sealed in the stability experiment, and the "open" condition means the condition in which the lid is opened.

The crystalline form of compound (I) disclosed in this specification is stable when exposed to conditions of about 70°C and about 75% relative humidity for about 2 weeks. In other words, the crystalline form of compound (I) disclosed in this specification exhibits long-term excellent storage stability. In this specification, "stable" means that the increase in impurities is about 1.0, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, or 0.01% or less compared to the initial impurity amount. The increase of impurities is preferably 1.0% or less, more preferably 0.5% or less, more preferably 0.4% or less, more preferably 0.3% or less, more preferably 0.2% or less, more preferably 0.1% or less, further preferably 0.05% or less, and particularly preferably 0.01% or less.

In certain embodiments, the crystalline form of Compound (I) disclosed in this specification may be physically and/or chemically highly pure. In certain embodiments, the crystals disclosed in this specification may be at least about 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81 or 80% physically and/or chemically pure. In some embodiments, the crystals disclosed in this specification are substantially pure. As used in this specification and unless otherwise specified, "substantially pure" means, for example, substantially free of other solid forms and/or other compounds. In specific embodiments, the crystals disclosed in this specification contain about 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or less than 0.1% by weight of one or more other solid forms and/or other compounds.

The free form I crystal of Compound (I) has, for example, a powder X-ray diffraction spectrum (CuKα) as shown in FIG1 , and a thermogravimetric-differential thermal analysis (TG-DTA) curve as shown in FIG2 .

Here, the characteristic peaks in the powder X-ray diffraction spectrum of the I-form crystal of the free form of Compound (I) can be exemplified by 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5° as diffraction angles (2θ±0.2°). More preferably, the characteristic peak in the powder X-ray diffraction spectrum (CuKα) of the I-type crystal of the free form of Compound (I) has diffraction angles (2θ±0.2°) of 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, 26.5° when measured by reflection method.

The free form I crystal of the compound (I) in one embodiment of the present invention has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα). (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5°

In a preferred embodiment of the present invention, the I-form crystal of the free form of the compound (I) has peaks at at least two angles selected from the group (a) above at a diffraction angle (2θ±0.2°), and has peaks at at least two angles selected from the group (b) above at a diffraction angle (2θ±0.2°). More preferably, the powder X-ray diffraction spectrum has peaks at at least three angles selected from the group (a) above at a diffraction angle (2θ±0.2°), and has peaks at at least two angles selected from the group (b) above at a diffraction angle (2θ±0.2°). More preferably, in the powder X-ray diffraction spectrum, there are peaks at at least 4 angles selected from the group (a) at diffraction angles (2θ±0.2°), and there are peaks at at least 2 angles selected from the group (b) at diffraction angles (2θ±0.2°). Further preferably, in the powder X-ray diffraction spectrum, there are peaks at at least 5 angles selected from the group (a), and there are peaks at at least 2 angles selected from the group (b) at diffraction angles (2θ±0.2°). It is particularly preferred that, in the powder X-ray diffraction spectrum, the diffraction angle (2θ±0.2°) has peaks at all angles selected from the group (a) above, and the diffraction angle (2θ±0.2°) has peaks at at least two angles selected from the group (b) above.

In other embodiments, the I-form crystals of the free form of Compound (I) in the preferred embodiments of the present invention have peaks at diffraction angles (2θ±0.2°) selected from at least 2 angles in the group (a) above in the powder X-ray diffraction spectrum, and have peaks at diffraction angles (2θ±0.2°) selected from at least 2 angles in the group (b) above, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, further preferably at least 11, further preferably at least 12, and particularly preferably at all angles.

In other embodiments, the I-form crystals of the free form of Compound (I) have peaks at at least 3 angles selected from the group (a) above at diffraction angles (2θ±0.2°), and have peaks at at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, further preferably at least 11, further preferably at least 12, and particularly preferably at all angles at diffraction angles (2θ±0.2°) selected from the group (b) above.

In other embodiments, the I-form crystals of the free form of Compound (I) have peaks at diffraction angles (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum, and have peaks at diffraction angles (2θ±0.2°) selected from the group (b) above at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, further preferably at least 11, further preferably at least 12, and particularly preferably at all the angles.

In other embodiments, the I-form crystals of the free form of Compound (I) have peaks at diffraction angles (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum, and have peaks at diffraction angles (2θ±0.2°) selected from the group (b) above at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, further preferably at least 11, further preferably at least 12, and particularly preferably at all the angles.

In other embodiments, the I-form crystals of the free form of Compound (I) have peaks at all angles of the diffraction angle (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum, and have peaks at at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, further preferably at least 11, further preferably at least 12, and particularly preferably at all angles of the diffraction angle (2θ±0.2°) selected from the group (b) above.

The endothermic peak in the thermogravimetric-differential thermal analysis (TG-DTA) curve of the free form of the I-type crystal of the compound (I) is, for example, around 233°C to 237°C, preferably around 235°C.

The chemical purity of the free form of compound (I) is 90% or more, which can be determined by high performance liquid chromatography (HPLC). Preferably, the chemical purity of the free form of compound (I) is 95% or more, and more preferably, the chemical purity is 99% or more.

The I-form crystals of the free body of compound (I) may be any crystals containing the I-form crystals of the free body, and may be single crystals of the I-form crystals of the free body, or may be a polymorphic mixture containing other crystals. Preferably, 90% or more of the I-form crystals of the free body are I-form crystals, and more preferably, 95% or more of the I-form crystals are I-form crystals.

By dissolving the crude product of Compound (I) in tetrahydrofuran and adding ethyl acetate, I-form crystals of a free form of Compound (I) can be obtained. However, in this case, the particle size obtained tends to become non-uniform. In the obtained non-uniform crystals, there are differences in the amount of similar substances and residual solvent contained in each of the flake portion that can be easily separated by a sieve with a pore size of 340 μm and the powder portion that has passed through the sieve. Although both are I-form crystals of a free form of Compound (I), it is more preferable to suppress the amount of residual solvent and produce I-form crystals of a free form of Compound (I) with high chemical purity with uniform quality.

In the industrial production of pharmaceuticals, as shown in the guidelines of ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), the amount of residual solvents is required to be as small as possible. The limit value of ethyl acetate is required to be 5000 ppm or less, the limit value of tetrahydrofuran is required to be 720 ppm or less, and the limit value of dimethyl sulfoxide is required to be 5000 ppm or less. The residual amount of ethyl acetate is preferably 5000 ppm or less, more preferably 4000 ppm or less, more preferably 3000 ppm or less, further preferably 2000 ppm or less, and particularly preferably 1000 ppm or less. The residual amount of tetrahydrofuran is preferably 720 ppm or less, more preferably 500 ppm or less, further preferably 300 ppm or less. The residual amount of dimethyl sulfoxide is preferably less than 5000 ppm, more preferably less than 3000 ppm.

The free form I crystal of the compound (I) of the present invention can be prepared, for example, by a method comprising the steps of dissolving the compound (I) in a solvent 1 (rich solvent) (step (1)), and adding a solvent 2 (poor solvent) to the solution obtained in step (1) to obtain a solid compound (I) (step (2).

As a preferred dissolving solvent (solvent 1) in step (1), dimethyl sulfoxide or tetrahydrofuran can be exemplified. More preferably, dimethyl sulfoxide is used. As a preferred solvent (solvent 2) added in step (2), when tetrahydrofuran is used in step (1), n-heptane, ethyl acetate or 2-propanol can be exemplified, and when dimethyl sulfoxide is used in step (1), water can be exemplified. Preferably, solvent 1 in step (1) is dimethyl sulfoxide, and solvent 2 in step (2) is water.

In step (2), in order to promote the crystallization, an appropriate amount of I-form crystals of the free form of compound (I) may or may not be added as seed crystals.

In step (1), the temperature for dissolving compound (I) can be appropriately set. For example, when compound (I) is dissolved in 20 v/w dimethyl sulfoxide, it is preferably room temperature to 70°C.

When dimethyl sulfoxide is used in step (1), in step (2), water can be added while the internal temperature is between room temperature and 70°C to precipitate the I-type crystals of the free form of compound (I). The temperature at this time is preferably maintained at 40 to 70°C, more preferably 60 to 70°C. The temperature of water when adding water in step (2) is more preferably 40 to 60°C. In addition, the amount of water added at this time is preferably 3 v/w or more relative to compound (I), more preferably 20 v/w to 25 v/w.

When water is used in step (2), the addition time of water can be 0.5 to 6 hours by slowly adding dropwise to obtain I-type crystals of the free form of compound (I). At this time, as is generally known in the art of crystallization, by increasing the addition rate, crystals with a smaller particle size can be obtained, and conversely, by decreasing the addition rate, crystals with a larger particle size can be obtained.

The precipitated crystals can be isolated and purified from the suspension containing the crystals by known separation and purification methods such as filtration, washing with water, and drying under reduced pressure.

The form II crystal of the free form of compound (I) has, for example, a powder X-ray diffraction spectrum as shown in FIG3 , and a thermogravimetric-differential thermal analysis (TG-DTA) curve as shown in FIG4 .

Here, the characteristic peaks in the X-ray diffraction spectrum (CuKα) of the crystalline powder of the form II crystal of the free form of Compound (I) can be exemplified by 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, and 27.9° as diffraction angles (2θ±0.2°). More preferably, the characteristic peak in the powder X-ray diffraction spectrum of the form II crystal of the free form of compound (I) has a diffraction angle (2θ±0.2°) of 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, 27.9° when measured by reflection method.

The free form II crystal of compound (I) in one embodiment of the present invention has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα). (a) 10.4°, 22.9° and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8° and 26.5°

In a preferred embodiment of the present invention, the form II crystal of the free form of compound (I) has peaks at diffraction angles (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum, and has peaks at diffraction angles (2θ±0.2°) selected from the group (b) above at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, further preferably at least 11, and particularly preferably all of the angles. In other embodiments of the present invention, the form II crystal of the free form of compound (I) may have peaks at all diffraction angles (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum.

In other embodiments, the form II crystals of the free form of compound (I) have peaks at all angles of the diffraction angle (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum, and have peaks at at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, further preferably at least 11, and particularly preferably at all angles of the diffraction angle (2θ±0.2°) selected from the group (b) above.

In addition, the endothermic peak in the thermogravimetric-differential thermal analysis (TG-DTA) curve of the free form of Compound (I) in form II crystals is exemplified to be around 232°C to 236°C, preferably around 234°C.

In one embodiment of the present invention, the form II crystal of the free form of compound (I) can be obtained, for example, by the following method, which comprises step (3) of adding compound (I) to a solvent to dissolve it, step (4) of heating and suspending it, and step (5) of cooling the solution of compound (I) to crystallize compound (I). In this embodiment, as the solvent in step (3), for example, methanol can be used. Methanol is preferred.

When methanol is used in step (4), the temperature of the heating suspension can be 50°C to 100°C, and the heating reaction time can be 0.5 to 48 hours. Preferably, the temperature is 50°C and the reaction time is 22 hours.

The crystallization in step (5) can be carried out under stirring. In this case, the stirring is appropriately carried out using a stirrer, a stirring blade, etc., depending on the amount of solvent, the size of the reaction vessel, etc. In addition, the stirring operation can also be carried out by, for example, vibrating the reaction vessel. The stirring speed is usually 1 to 600 rpm, preferably 10 to 100 rpm. In step (5), the temperature during cooling can be carried out at room temperature, preferably at room temperature.

The chemical purity of the free form II crystal of compound (I) obtained in the above manner is 90% or more, which can be determined by high performance liquid chromatography (HPLC). Preferably, the chemical purity of the free form II crystal of compound (I) is 95% or more, and more preferably, the chemical purity is 99% or more.

The form II crystals of the free body of compound (I) may be any crystals containing the form II crystals of the free body, and may be single crystals of the form II crystals of the free body, or may be a polymorphic mixture containing other crystals. Preferably, 90% or more of the form II crystals of the free body are the form II crystals of the free body, and more preferably, 95% or more of the form II crystals of the free body are the form II crystals of the free body.

The III-form crystal of the free form of Compound (I) has, for example, a powder X-ray diffraction spectrum as shown in FIG5 , and a thermogravimetric-differential thermal analysis (TG-DTA) curve as shown in FIG6 .

Here, the characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the III-form crystal of the free form of Compound (I) can be exemplified by 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, and 26.7° as diffraction angles (2θ±0.2°). More preferably, the characteristic peaks in the powder X-ray diffraction spectrum of the III-form crystal of the free form of compound (I) have diffraction angles (2θ±0.2°) of 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, 26.7° when measured by reflection method. The III-form crystal of the free form of compound (I) in one embodiment of the present invention has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα).

(a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7°

In a preferred embodiment of the present invention, the III-form crystal of the free form of Compound (I) has peaks at diffraction angles (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum, and has peaks at diffraction angles (2θ±0.2°) selected from the group (b) above at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, more preferably at least 11, more preferably at least 12 or more, further preferably at least 13, and particularly preferably all of the angles. In other embodiments of the present invention, the III-form crystals of the free form of Compound (I) may have peaks at all diffraction angles (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum.

In other embodiments, the free form III crystals of Compound (I) have peaks at all angles of the diffraction angle (2θ±0.2°) selected from the group (a) above in the powder X-ray diffraction spectrum, and have peaks at at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, more preferably at least 8, more preferably at least 9, more preferably at least 10, more preferably at least 11, more preferably at least 12, further preferably at least 13, and particularly preferably at all angles of the diffraction angle (2θ±0.2°) selected from the group (b) above.

In addition, the endothermic peak in the thermogravimetric-differential thermal analysis (TG-DTA) curve of the free form of compound (I) in form III can be exemplified to be around 232°C to 236°C, preferably around 234°C.

In one embodiment of the present invention, the type III crystal of compound (I) can be obtained, for example, by a method comprising adding compound (I) to a solvent and performing heating circulation, and then performing rapid cooling to crystallize, step (7). In this embodiment, as the solvent in step (6), for example, ethanol, 2-methyltetrahydrofuran, etc. can be used alone, or a mixed solvent of ethanol and 2-methyltetrahydrofuran can be used. Ethanol is preferred.

The crystallization in step (7) can be carried out under stirring. In this case, stirring is carried out using a stirrer, a stirring blade, etc., as appropriate according to the amount of solvent, the size of the reaction vessel, etc. In addition, the stirring operation can also be carried out by, for example, vibrating the reaction vessel, etc. The stirring speed is usually 1 to 600 rpm, preferably 10 to 100 rpm.

The chemical purity of the free form III crystal of compound (I) obtained in the above manner is 90% or more, which can be determined by high performance liquid chromatography (HPLC). Preferably, the chemical purity of the free form III crystal of compound (I) is 95% or more, and more preferably, the chemical purity is 99% or more.

The III-form crystals of the free body of Compound (I) may be single crystals of the III-form crystals of the free body or a polymorphic mixture including other crystals. Preferably, 90% or more of the III-form crystals of the free body are the III-form crystals of the free body, and more preferably, 95% or more of the III-form crystals of the free body are the III-form crystals of the free body.

The crystals of the hydrochloride of compound (I) have, for example, a powder X-ray diffraction spectrum as shown in FIG7 , and a thermogravimetric-differential thermal analysis (TG-DTA) curve as shown in FIG8 . Here, the characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the crystals of the hydrochloride of compound (I) can be exemplified as diffraction angles (2θ±0.2°) of 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6°. More preferably, the characteristic peaks in the powder X-ray diffraction spectrum of the crystal of the hydrochloride of compound (I) have diffraction angles (2θ±0.2°) of 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, 31.6° when measured by reflection method.

The crystals of the hydrochloride of compound (I) of the present invention are selected from at least 3 peaks selected from the above peaks, for example, crystals having at least 3 peaks selected from the above peaks, preferably crystals having at least 4 peaks selected from the above peaks, more preferably crystals having at least 5 peaks selected from the above peaks, more preferably crystals having at least 6 peaks selected from the above peaks, more preferably crystals having at least 7 peaks selected from the above peaks, more preferably crystals having at least 8 peaks selected from the above peaks, and more preferably crystals having at least 1 peak selected from the above peaks. The crystals have at least 9 peaks selected from the above peaks, more preferably at least 10 peaks selected from the above peaks, more preferably at least 11 peaks selected from the above peaks, more preferably at least 12 peaks selected from the above peaks, more preferably at least 13 peaks selected from the above peaks, more preferably at least 14 peaks selected from the above peaks, more preferably at least 15 peaks selected from the above peaks, and particularly preferably all of the above peaks.

In addition, the endothermic peak in the thermogravimetric-differential thermal analysis (TG-DTA) curve of the crystals of the hydrochloride salt of Compound (I) is exemplified to be around 239°C to 243°C, preferably around 241°C.

In one embodiment of the present invention, the crystals of the hydrochloride of compound (I) can be obtained, for example, by a method comprising the following step (8), i.e., adding compound (I) to a solvent, adding hydrochloric acid, and stirring at room temperature to crystallize. In this embodiment, the solvent in step (8) can be, for example, ethyl acetate, methanol, ethanol, or a mixed solvent thereof. A mixed solvent of ethyl acetate and methanol is preferred.

The crystallization in step (8) can be carried out under stirring. In this case, stirring is carried out using a stirrer, a stirring blade, etc., as appropriate according to the amount of solvent, the size of the reaction vessel, etc. The stirring operation can also be carried out, for example, by vibrating the reaction vessel. The stirring speed is usually 1 to 600 rpm, preferably 10 to 100 rpm.

The amount of hydrochloric acid added in step (8) may be 0.9 to 1.1 molar equivalents relative to the amount of compound (I), preferably 1.0 molar equivalent.

The chemical purity of the crystalline hydrochloride of Compound (I) obtained in the above manner is 90% or more, which can be determined by high performance liquid chromatography (HPLC). Preferably, the chemical purity of the crystalline hydrochloride of Compound (I) is 95% or more, and more preferably, the chemical purity is 99% or more.

The crystals of the hydrochloride of Compound (I) may be crystals of the hydrochloride, and may be single crystals of the hydrochloride, or a polymorphic mixture including other crystals. Preferably, 90% by weight or more of the crystals are crystals of the hydrochloride, and more preferably, 95% or more of the crystals are crystals of the hydrochloride.

The crystals of the maleic acid salt of Compound (I) have, for example, a powder X-ray diffraction spectrum as shown in FIG9 and a thermogravimetric-differential thermal analysis (TG-DTA) curve as shown in FIG10 .

Here, the characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the crystal of the maleic acid salt of Compound (I) can be exemplified by 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8° as diffraction angles (2θ±0.2°). More preferably, the characteristic peak in the powder X-ray diffraction spectrum of the crystal of the maleic acid salt of compound (I) has a diffraction angle (2θ±0.2°) of 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, 30.8° when measured by reflection method.

The crystals of the maleic acid salt of compound (I) of the present invention are selected from at least 3 peaks selected from the above peaks, for example, crystals having at least 3 peaks selected from the above peaks, preferably crystals having at least 4 peaks selected from the above peaks, more preferably crystals having at least 5 peaks selected from the above peaks, more preferably crystals having at least 6 peaks selected from the above peaks, more preferably crystals having at least 7 peaks selected from the above peaks, more preferably crystals having at least 8 peaks selected from the above peaks, more preferably crystals having at least 9 peaks selected from the above peaks, more preferably crystals having at least 10 peaks selected from the above peaks, more preferably crystals having at least 10 peaks selected from the above peaks. The crystals have at least 11 peaks selected from the above peaks, more preferably at least 12 peaks selected from the above peaks, more preferably at least 13 peaks selected from the above peaks, more preferably at least 14 peaks selected from the above peaks, more preferably at least 15 peaks selected from the above peaks, more preferably at least 16 peaks selected from the above peaks, more preferably at least 17 peaks selected from the above peaks, more preferably at least 18 peaks selected from the above peaks, more preferably at least 19 peaks selected from the above peaks, and particularly preferably all of the above peaks.

In addition, the endothermic peak in the thermogravimetric-differential thermal analysis (TG-DTA) curve of the crystal of the maleic acid salt of Compound (I) can be exemplified to be around 243°C to 247°C, preferably around 245°C.

In one embodiment of the present invention, the crystallization of the maleic acid salt of compound (I) can be obtained, for example, by a method comprising the following steps: step (10) of adding compound (I) and maleic acid to a solvent, heating and stirring to obtain an amorphous body, step (11) of heating and circulating the obtained amorphous body, and step (12) of stirring at room temperature and then cooling in an ice bath to crystallize the amorphous body. In this embodiment, as the solvent in step (10), for example, chloroform, methanol, etc. or a mixed solvent thereof can be used. Preferably, a mixed solvent of chloroform and methanol is used. In step (11), as the solvent used, for example, acetonitrile can be used. In step (11), the reaction can be carried out at a temperature near the boiling point of the solvent, preferably 85°C when the solvent is acetonitrile.

The amount of maleic acid added in step (10) must be the same molar equivalent relative to the amount of compound (I).

The crystallization in step (9) can be carried out under stirring. In this case, stirring is carried out using a stirrer, a stirring blade, etc. appropriately according to the amount of solvent, the size of the reaction vessel, etc. The stirring operation can also be carried out by, for example, vibrating the reaction vessel, etc.

The chemical purity of the maleic acid salt crystals of Compound (I) obtained in the above manner is 90% or more, which can be determined by high performance liquid chromatography (HPLC). Preferably, the chemical purity of the maleic acid salt crystals of Compound (I) is 95% or more, and more preferably, the chemical purity is 99% or more.

The crystals of the maleic acid salt of compound (I) may be any crystals containing the maleic acid salt, and may be single crystals of the maleic acid salt or a polymorphic mixture containing other crystals. Preferably, 90% or more of the crystals are the maleic acid salt, and more preferably, 95% or more of the crystals are the maleic acid salt.

The above is a description of one embodiment of obtaining the crystal form (I-form crystal, II-form crystal, III-form crystal), the crystal of the hydrochloride salt, and the crystal of the maleic acid salt of the free form of the compound (I) of the present invention, but this is only an example. The crystal form (I-form crystal, II-form crystal, III-form crystal), the crystal of the hydrochloride salt, and the crystal of the maleic acid salt of the free form of the compound (I) of the present invention is not limited to those obtained by the above-exemplified embodiment. The industry can use known technical methods to produce the crystal form (I-form crystal, II-form crystal, III-form crystal), the crystal of the hydrochloride salt, and the crystal of the maleic acid salt of the free form of the compound (I) of the present invention.

As shown in the following examples, the free form of compound (I) of the present invention, the crystals of form I, form II, form III, the crystals of the hydrochloride of compound (I) and the crystals of the maleic acid salt of compound (I) have low hygroscopicity and excellent solid stability (storage stability, etc.). It is particularly important for the raw materials of pharmaceuticals or the active ingredients in pharmaceuticals to have solid stability in terms of industrial operation and quality maintenance.

Furthermore, solvents used in the manufacture of pharmaceuticals may be toxic. From the viewpoint of safety, it is desirable that the amount of residual solvents in the manufacturing steps be as small as possible. The I-form crystals of the free form of Compound (I) do not contain residual solvents exceeding the limit value of the ICH (International Conference on Harmonization of Pharmaceutical Controls, Japan, the United States and the European Union) guidelines.

The free form of compound (I) of the present invention in the form of I crystals, II crystals, III crystals, hydrochloride crystals and maleate crystals has excellent anti-tumor effect and is useful as a pharmaceutical for treating tumors.

When the free form of compound (I) in the form I, II, III, hydrochloride or maleate forms is used as a medicine, the crystals may be pulverized or not, and various administration forms may be adopted according to the purpose of prevention or treatment. The form may be, for example, oral preparations such as tablets, capsules, granules, fine granules, powders, dry syrups, and non-oral preparations such as suppositories, inhalants, nasal drops, ointments, patches, injections, etc., preferably oral preparations. The pharmaceutical compositions may be produced using pharmaceutically acceptable carriers and conventional preparation methods known to the industry.

As pharmaceutical carriers, various conventional organic or inorganic carrier substances are used as raw materials for preparations, and are formulated as excipients, binders, disintegrants, lubricants, coating agents in solid preparations, solvents, dissolution aids, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid preparations. In addition, preparation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. may also be used as necessary.

Examples of excipients include lactose, white sugar, D-mannitol, starch, crystalline cellulose, calcium silicate, etc. Examples of binders include hydroxypropyl cellulose, methyl cellulose, polyvinyl pyrrolidone, starch, hydroxypropyl methyl cellulose, etc. Examples of disintegrants include sodium glycolate starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvidone, low-substituted hydroxypropyl cellulose, partially alpha-starched starch, etc.

Examples of lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, sodium stearyl fumarate, etc. Examples of coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hydroxypropyl methylcellulose, white sugar, etc. Examples of solvents include water, propylene glycol, and physiological saline. Examples of dissolving aids include polyethylene glycol, ethanol, α-cyclodextrin, polyethylene glycol 400, polysorbate 80, etc.

Examples of suspending agents include carrageenan, crystalline cellulose, sodium carboxymethyl cellulose, and polyoxyethylene hydrogenated castor oil. Examples of isotonic agents include sodium chloride, glycerol, and potassium chloride. Examples of pH adjusters and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, and sodium dihydrogen phosphate. Examples of analgesics include procaine hydrochloride and lidocaine.

Examples of preservatives include ethyl paraben, cresol, benzyl ammonium chloride, etc. Examples of antioxidants include sodium sulfite, ascorbic acid, natural vitamin E, etc. Examples of colorants include titanium oxide, ferric oxide, brilliant blue FCF, copper chlorophyll, etc. Examples of flavor and odor control agents include aspartame, saccharin, sucralose, l-menthol, mint flavor, etc. Examples of stabilizers include sodium metabisulfite, sodium ethylenediaminetetraacetate, isoascorbic acid, magnesium oxide, dibutylhydroxytoluene, etc.

In the case of preparing a solid preparation for oral use, a forming agent, and optionally a binder, disintegrant, lubricant, colorant, taste and deodorant, etc. are added to the free form of Compound (I) in the form I crystals, form II crystals, form III crystals, hydrochloride salt crystals or maleic acid salt crystals, and then tablets, coated tablets, granules, powders, capsules, etc. can be prepared according to conventional practices.

The amount of the free form of compound (I) in the form I crystal, form II crystal, form III crystal, hydrochloride crystal and maleate crystal to be formulated in each administration unit is not fixed depending on the symptoms of the patient to whom it is applied, its dosage form, etc., but is usually expected to be about 0.05 to 1000 mg for oral dosage, about 0.1 to 500 mg for injection, and about 1 to 1000 mg for suppository or external preparation per administration unit.

In addition, the daily dosage of the free form of Compound (I) in the form I crystal, form II crystal, form III crystal, hydrochloride crystal and maleic acid salt crystal of the drug having each administration mode varies depending on the patient's symptoms, weight, age, sex, etc., and cannot be determined in general. However, generally, an adult (weight 50 kg) can be treated with Compound (I) or a pharmaceutically acceptable salt thereof at a dosage level of about 20 mg/day, about 40 mg/day, about 60 mg/day, about 80 mg/day, about 100 mg/day, about 200 mg/day, or about 300 mg/day for intermittent administration. The dosage may be about 400 mg/day, about 500 mg/day, about 600 mg/day, about 3000 mg/day, about 2,500 mg/day, about 2,000 mg/day, about 1,500 mg/day, about 1,000 mg/day, about 900 mg/day, about 800 mg/day, about 700 mg/day, or any dosage level within these ranges. Preferably, the dosage is divided into once or 2 to 3 times a day for administration.

Regarding the administration of compound (I) or a pharmaceutically acceptable salt thereof (preferably a hydrochloride or a maleate), it can be administered continuously (administered for 7 days in a week) or intermittently, for example, according to the pharmacokinetics and the clearance/accumulation of the drug in a specific subject. In the case of intermittent administration, for example, a schedule of 4 days of administration and 3 days of drug withdrawal in a week can be adopted, or other intermittent administration schedules deemed appropriate using reasonable medical judgment can be adopted, preferably continuous administration. Administration can be performed once a day (QD) or twice or more a day (b.i.d., t.i.d., etc.), preferably a dose of about 20 to 960 mg/day QD. The daily dose may be a single administration or multiple separate administrations. For example, two tablets containing 40 mg of compound (I) or a pharmaceutically acceptable salt thereof (preferably a hydrochloride or a maleate) may be administered to a subject once a day (QD) at a total dose of 80 mg/day. In one embodiment, two tablets each containing 40 mg of compound (I) or a pharmaceutically acceptable salt thereof (preferably a hydrochloride or a maleate) may be administered to a subject twice a day (b.i.d) at a total dose of 160 mg/day. The amount of compound (I) or a pharmaceutically acceptable salt thereof administered is the amount converted to the amount of compound (I).

Whether continuous or intermittent, administration continues with a specific treatment cycle, typically a cycle of at least 28 days, which can be repeated with or without interruptions in the medication. Longer or shorter cycles of 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 days, or any range in between can also be used. The cycle can be repeated with or without a break, depending on the subject. Other schedules can also be used, depending on the presence or absence of adverse events, the response of the cancer to treatment, the convenience of the patient, etc. "Adverse events" refer to unpleasant or unexpected diseases or symptoms that occur in patients who have been administered a drug. This is true regardless of whether there is a causal relationship with the drug. In the case of intermittent administration, for example, it can be administered on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, or on days 1, 4, 8, 11, 15, 19, 23, 27, or on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in a cycle of days 1, 4, 8, 11, 15, 19, 23, 27, and 28.

The powder X-ray diffraction measurement method of the crystals of Compound (I) of the present invention can be carried out by using the reflection method.

In general, the morphology of many crystalline particles has a tendency to impart a selective orientation to the sample in the sample holder. The selective orientation in the sample affects the intensity of various reflections, resulting in reflections being observed to be stronger in some cases and weaker in others than would be expected in a completely unoriented sample. [Example]

The following examples are given to more specifically illustrate the present invention, but the present invention is not limited thereto. It is understood that the present invention is fully illustrated by the examples, but the industry can make various changes and/or modifications. Therefore, such changes and/or modifications are included in the present invention as long as they do not deviate from the scope of the present invention.

<Reagents and measurement methods> All reagents used in the examples were commercially available unless otherwise specified. NMR spectroscopy was performed using AL400 (400 MHz, JEOL). When tetramethylsilane was contained in the deuterated solvent, tetramethylsilane was used as the internal standard. In other cases, the residual non-deuterated proton peak in the NMR solvent was used as the internal standard for measurement. The total δ value was expressed in ppm.

The meanings of the abbreviations are shown below. s: singlet d: doublet t: triplet dd: doublet of doublets m: multiplet brs: broad singlet DMSO-d ₆ : deuterated dimethyl sulfoxide CDCl ₃ : deuterated chloroform

Powder X-ray diffraction measurement Powder X-ray diffraction is to gently crush an appropriate amount of test material in an agate mortar as needed, and then measure it according to the following test conditions.

Device: Panalytical Empyrean Target: Cu X-ray output setting: 40 mA, 45 kV Scanning range: 2.0～40.0° Step: 0.026° Measurement method: Reflection method

The operation of the devices including data processing is in accordance with the methods and sequences indicated in each device. Furthermore, the values obtained from various spectra may sometimes vary slightly due to the direction of crystal growth, particle size, measurement conditions, etc. Therefore, these values should not be interpreted strictly.

Thermogravimetric-differential thermal analysis (TG-DTA) TG-DTA is performed under the following test conditions. Device: Hitachi High-Tech Science TG/DTA7200 Sample: Approximately 5 mg Sample container: Aluminum Heating rate: 10°C/min to 300°C Ambient gas: Air Nitrogen flow rate: 100 mL/min The operation of the devices including data processing is in accordance with the methods and sequences indicated in each device.

Residual solvent determination The residual solvent is determined according to the following test conditions.

Measured objects: ethyl acetate, tetrahydrofuran 〈GC (gas chromatograph, gas chromatography) conditions〉 Device: Shimadzu GC-2010 Plus Detector: FID (Flame Ionization Detector) Column: Inert Cap-5 Science (0.53 mm×30 m, 5 μm) Column temperature: 40°C for 10 minutes, then increase the temperature to 110°C at 2°C per minute, then increase the temperature to 250°C at 30°C per minute for 15 minutes Injection temperature: 260°C Detection temperature: 260°C Ambient gas: He Linear velocity: 28 cm/min Gas flow rate: 400 mL/min Helium flow rate: 50 mL/min Auxiliary rate: 50 mL/min Auxiliary gas: He

<HS conditions> HS oven temperature: 80℃ HS needle temperature: 90℃ Transfer temperature: 100℃ Measurement time: 30 min Compression time: 3/min Pulling up time: 0.2/min Injection time: 0.1/min GC cycle time: 80/min

Target: Dimethyl sulfoxide 〈GC (gas chromatography) conditions〉 Detector: FID Column: Inert Cap Pure-WAX, GLScience (30 m×0.53 mm×5 μm) Column temperature: 35°C for 5 minutes, then 5°C/min to 80°C, then 3°C/min to 170°C, then 20°C/min to 230°C for 10 minutes Injection temperature: 240°C Detection temperature: 240°C Ambient gas: He Flow rate: 28 cm/min Split ratio: 10:1 Injection volume: 1 μL Detection gas flow rate: H2: 50 ml/min, Air: 400 mL/min, N2: 45 mL/min The operation of devices involving data processing is in accordance with the methods and sequences indicated in each device.

Example 1 Preparation of I- form crystals of the free form of compound (I) Compound (I) (11.7 g) synthesized according to the method described in International Publication No. 2017/200087 (Example 32) was suspended in ethyl acetate (110 mL) and stirred at 100° C. for 4 hours, and then stirred at room temperature for 18 hours. The suspension was filtered, and the obtained powder (10.4 g) was suspended in ethyl acetate (220 mL) again. The suspension was stirred at 100° C. for 5 hours, and then stirred at room temperature for 9 hours. The suspension was filtered to obtain I-form crystals of the free form of compound (I) (9.37 g) with a yield of 80.1% and a chemical purity of 97.31%.

The ¹ H-NMR spectrum of the obtained I-form crystals of Compound (I) is shown below. ¹ H-NMR (DMSO - D6) δ: 8.23 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 8.8 Hz), 6.45 (1H, t, J = 5.2 Hz), 4.49 (2H, d, J = 13.2 Hz), 3.22 (5H, m, 3.29 - 3.13), 2.71 (2H, t, J = 6.7 Hz), 1.93 (2H, d, J = 12.0 Hz), 1.76 (2H, m, 1.82 - 1.70), 1.39 (6H, s), 1.03 (9H, s)

In addition, from the ¹ H-NMR spectrum, it was calculated that about 5700 ppm of ethyl acetate was contained as a residual solvent. The residual amount of the solvent from the ¹ H-NMR spectrum was calculated by converting the molecular weight into a weight ratio based on the ratio of the integral value of the peak derived from compound (I) to the solvent peak, and the weight of the solvent ÷ (weight of compound (I) + weight of the solvent).

The powder X-ray diffraction spectrum and thermogravimetric-differential thermal analysis (TG-DTA) curve of the obtained free body I-type crystal are shown below. Powder X-ray diffraction spectrum: shown in Figure 1. The characteristic diffraction angle is shown below.

Characteristic diffraction angle (2θ±0.2°): 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, 26.5° The peaks are shown in the following table (Table 1).

[Table 1] Table 1 Peak position (°2θ) Strength (cts) Peak position (°2θ) Strength (cts) 6.2 554.1 25.1 947.3 6.7 413.2 25.4 578.1 8.3 538.2 25.9 868.6 8.7 383.4 26.5 746.0 9.3 1789.2 27.1 198.9 9.7 586.9 27.6 197.2 10.3 139.5 27.9 54.8 11.1 1477.5 28.3 208.7 12.5 421.8 29.0 91.2 13.0 973.0 29.2 65.8 13.7 675.3 29.9 180.8 14.0 381.0 30.9 113.0 15.4 1308.0 31.4 25.9 16.3 7208.6 32.9 88.7 16.9 599.8 34.5 59.5 17.7 811.9 35.3 22.9 18.3 194.0 36.0 29.7 18.7 872.3 36.5 100.7 19.4 1669.6 36.9 39.7 20.3 2021.3 37.7 14.9 20.8 563.4 38.0 18.5 21.3 443.1 38.5 13.9 21.9 591.3 38.9 17.8 23.0 464.8 39.4 53.6 23.6 191.6 24.0 151.5 24.7 115.3

Thermogravimetric-differential thermal analysis (TG-DTA) curve: shown in Figure 2.

Preparation Example 1 Preparation of I -form crystals of the free form of compound (I) The I-form crystals of the free form of compound (I) can also be prepared according to the following method. In an oil bath at 110°C, the compound (I) (6.0 g) synthesized according to the method described in International Publication No. 2017/200087 (Example 32) was stirred in a mixed solvent of tetrahydrofuran (42 mL) and ethyl acetate (210 mL) under heating reflux for 1 hour to dissolve it. The internal temperature at this time was 75°C. Remove the oil bath and stir at room temperature for 3 hours to crystallize the compound (I). The internal temperature of the suspension at this time was 30°C. The suspension was filtered and dried under reduced pressure at 65° C. for 10 hours to obtain form I crystals of the free form of compound (I) (3.83 g, yield 64%).

The obtained compound (I) (20.00 g) was suspended in dimethyl sulfoxide (400 mL, 20 v/w) and stirred. After degassing at room temperature for 5 minutes, nitrogen was introduced. The obtained suspension was heated and stirred in an oil bath at 65°C for 25 minutes to dissolve the crude compound (I) to prepare a light yellow solution. The internal temperature at this time was 59°C.

The solution was clarified and filtered using a Glass-Fiber Filter (Whatman, GF/B, Φ60 mm), and the container was rinsed with 20 mL (1 v/w) of dimethyl sulfoxide. The temperature of the filtrate was 40°C at this time. The filtered filtrate was heated and stirred again in an oil bath at 65°C until the internal temperature reached 58°C, and then water (420 mL, 21 v/w) was added to crystallize. The crystallization of compound (I) began around the time water (70 mL, 3.5 v/w) was added dropwise for 4 hours, and the internal temperature was around 63°C at this time.

Afterwards, water (350 mL, 17.5 v/w) was added dropwise over 70 minutes to further promote crystallization. After the addition of water was completed, the suspension was stirred at an internal temperature of 67°C for 1 hour, and then cooled to room temperature over 3 hours while stirring.

The obtained suspension was filtered through Kiriyama filter paper (2 sheets, No.3, Φ95 mm (upper) and No.4, Φ95 mm (lower)), and the filtered wet crystals of compound (I) were washed with water (300 mL, 15 v/w).

The obtained wet crystals of crystals I of compound (I) were dried under reduced pressure at 70°C for 14 hours to obtain light yellow I-type crystals of free form of compound (I) (19.13 g, yield 96%, chemical purity 99.12%). In addition, according to the ¹ H-NMR spectrum, it was calculated that about 2400 ppm of dimethyl sulfoxide was contained in the form of residual solvent, but ethyl acetate and tetrahydrofuran were not detected. The amount of residual solvent was calculated in the same manner as in Example 1. The residual solvent was further analyzed by GC, which was dimethyl sulfoxide (2629 ppm), tetrahydrofuran (ND), and ethyl acetate (ND). In addition, ND means below the limit of quantification. The values below the limit of quantification of each solvent in the GC analysis were set to 235 ppm for dimethyl sulfoxide, 900 ppm for ethyl acetate, and 145 ppm for tetrahydrofuran.

Example 2 Preparation of Form II Crystals of Free Form of Compound (I) 40 mL of methanol was added to 2.00 g of compound (I) synthesized according to the method described in International Publication No. 2017/200087, and the mixture was heated, suspended and stirred at 50°C for 22 hours. The mixture was then cooled and stirred at room temperature for 2 hours and the solid was filtered out. After drying under reduced pressure at 40°C for 20 hours, 1.883 g (yield 94%) of Form II crystals of free form of compound (I) were obtained. The ¹ H-NMR spectrum of the obtained Form II crystals of free form of compound (I) is shown below.

¹ H-NMR (DMSO - d6) δ: 8.22 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 8.8 Hz), 6.41 (1H, t, J = 5.2 Hz), 4.49 (2H, d, J = 13.6 Hz), 3.30 - 3.14 (5H, m), 2.71 (2H, t, J = 6.7 Hz), 1.92 (2H, d, J = 12.0 Hz), 1.80 - 1.70 (2H, m), 1.39 (6H, s), 1.03 (9H, s).

The powder X-ray diffraction spectrum and thermogravimetric-differential thermal analysis (TG-DTA) curves of the obtained free body II-type crystals are shown below. Powder X-ray diffraction spectrum: shown in Figure 3.

The characteristic diffraction angles are shown below. Characteristic diffraction angles (2θ±0.2°): The diffraction angles (2θ±0.2°) are 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, and 27.9°. The peaks are shown in the following table (Table 2).

[Table 2] Table 2 Peak position (°2θ) Strength (cts) 3.6 87.6 6.7 1672.4 7.5 1513.6 8.5 135.2 10.4 634.7 12.7 297.3 13.4 389.4 14.6 916.0 15.9 99.4 16.5 857.4 17.1 94.1 17.9 349.1 18.3 256.7 19.0 65.7 19.8 605.3 20.6 215.8 21.8 301.1 22.4 108.1 22.9 418.5 24.0 123.4 24.2 76.3 24.7 95.2 25.9 61.1 26.5 409.5 27.3 62.1 27.9 260.1 29.8 109.0 31.0 89.3 32.2 28.6 34.2 21.6 35.4 40.3 38.9 24.3

Thermogravimetric-differential thermal analysis (TG-DTA) curve: shown in Figure 4.

Example 3 Preparation of III -form crystals of the free form of compound (I) 28 mL of ethanol was added to 500 mg of compound (I) synthesized according to the method described in International Publication No. 2017/200087, and the mixture was heated and circulated at an internal temperature of about 78°C. After dissolution was confirmed, the mixture was rapidly cooled in a dry ice-methanol bath. (About 1 minute after the start of cooling, the internal temperature was -2°C) After confirming the precipitation of crystals, the mixture was switched to a water bath, stirred at an internal temperature of about 0°C for 30 minutes, and the solid was filtered out. After drying under reduced pressure at 40°C for 20 hours, 347 mg of III-form crystals of the free form of compound (I) were obtained (yield 69%). The ¹ H-NMR spectrum of the III-form crystals of the free form of compound (I) obtained is shown below.

¹ H-NMR (DMSO - d6) δ: 8.23 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.10 (1H, d, J = 8.8 Hz), 6.44 (1H, t, J = 5.2 Hz), 4.50 (2H, d, J = 13.6 Hz), 3.41 - 3.14 (5H, m), 2.73 (2H, t, J = 6.7 Hz), 1.94 (2H, d, J = 12.0 Hz), 1.85 - 1.72 (2H, m), 1.40 (6H, s), 1.05 (9H, s).

The powder X-ray diffraction spectrum and thermogravimetric-differential thermal analysis (TG-DTA) curves of the obtained free body III-type crystals are shown below. Powder X-ray diffraction spectrum: shown in Figure 5.

The characteristic diffraction angles are shown below. Characteristic diffraction angles (2θ±0.2°): The diffraction angles (2θ±0.2°) are 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, and 26.7°. The peaks are shown in the following table (Table 3).

[Table 3] Table 3 Peak position (°2θ) Strength (cts) 2.9 107.7 6.8 834.4 7.5 1302.6 8.8 184.9 10.4 112.6 11.7 408.5 12.9 227.1 13.4 78.6 13.9 153.7 14.9 681.0 16.7 457.0 17.8 391.2 18.8 118.1 19.7 147.3 20.7 370.2 22.0 710.6 22.9 104.5 23.4 151.4 24.2 228.2 26.2 157.7 26.7 196.5 27.8 47.2 28.8 73.1 29.8 80.2 30.6 67.0 32.1 26.9 33.8 21.6 35.1 31.1 38.0 15.9

Thermogravimetric-differential thermal analysis (TG-DTA) curve: shown in Figure 6.

Example 4 Preparation of crystals of the hydrochloride of compound (I) To compound (I) (202 mg) synthesized according to the method described in International Publication No. 2017/200087, 3 ml of ethyl acetate and 3 ml of methanol were added and stirred, and then 71 ul of 5M aqueous hydrochloric acid solution (1 molar equivalent relative to compound (I)) was added and stirred at room temperature for 2 hours. The solid was filtered out and dried under reduced pressure to obtain crystals of the hydrochloride of compound (I) (161 mg) (yield 75%). The ¹ H-NMR spectrum of the obtained crystals of the hydrochloride of compound (I) is shown below. ¹ H-NMR (DMSO - d6) δ: 11.10 (1H, s), 8.96 (1H, br s), 8.22 (1H, s), 7.96 (1H, d, J = 8.8 Hz), 7.18 (1H, d, J = 8.8 Hz), 6.79 (1H, br s), 4.48 (2H, d, J = 13.6 Hz), 3.35 - 3.19 (5H, m), 2.71 (2H, t, J = 6.7 Hz), 1.95 - 1.75 (4H, m), 1.39 (6H, s), 1.31 (9H, s).

The powder X-ray diffraction spectrum and thermogravimetric-differential thermal analysis (TG-DTA) curves of the obtained hydrochloric acid salt crystals are shown below. Powder X-ray diffraction spectrum: shown in Figure 7.

The characteristic diffraction angles are as follows. Characteristic diffraction angles (2θ±0.2°): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, 31.6° Thermogravimetric-differential thermal simultaneous measurement was performed according to the test conditions of TG-DTA measurement described in the above "<Reagents and measurement methods>". However, the temperature was increased at a rate of 10°C/min to 400°C. The peaks are shown in the following table (Table 4).

[Table 4] Table 4 Peak position (°2θ) Strength (cts) 6.7 62.6 7.4 75.8 8.1 4.8 10.4 192.9 11.2 70.3 12.6 113.7 13.5 12.6 14.1 153.1 15.1 15.9 16.6 84.6 17.8 18.0 18.3 18.5 20.0 58.9 21.1 53.9 22.0 54.2 22.6 26.3 23.2 57.7 24.5 56.9 26.4 40.4 26.8 16.0 27.2 16.6 28.0 19.9 28.4 11.9 30.0 20.4 30.4 15.5 31.6 22.4 32.0 6.3 33.7 5.6 34.6 9.5 35.5 3.4

Thermogravimetric-differential thermal analysis (TG-DTA) curve: shown in FIG8 .

Example 5 Preparation of Crystals of Maleic Acid Salt of Compound (I ) 20 mL of chloroform/methanol (9/1) was added to compound (I) (2.0 g) synthesized according to the method described in International Publication No. 2017/200087 to dissolve it. 405 mg of maleic acid (1 molar equivalent relative to compound (I)) was added thereto and heated and stirred at 45°C. After confirming the dissolution, the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure at 40°C to obtain 2.43 g of maleic acid salt amorphous (yield 101%, residual CHCl ₃ ). Add 200 mL of acetonitrile to 500 mg of maleic acid salt amorphous solid and heat and circulate to dissolve. Cool and stir at room temperature. When the internal temperature reaches near room temperature, cool in an ice bath. Stir for 1 hour and filter out the solid. Dry under reduced pressure at 40°C to obtain 332 mg of maleic acid salt crystals (yield 66%).

The ¹ H-NMR spectrum of the obtained crystals of maleic acid salt of Compound (I) is shown below.

¹ H-NMR (DMSO - d6) δ: 11.12 (1H, s), 8.39 (1H, s), 7.99 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.8 Hz), 6.55 (1H, t, J = 5.2 Hz), 6.00 (2H, s), 4.50 (2H, d, J = 13.6 Hz), 3.60 - 3.07 (7H, m), 1.91 (2H, d, J = 12.0 Hz), 1.80 - 1.70 (2H, m), 1.39 (6H, s), 1.03 (9H, s).

The powder X-ray diffraction spectrum and thermogravimetric-differential thermal analysis (TG-DTA) curves of the obtained maleic acid salt crystals are shown below. Powder X-ray diffraction spectrum: shown in Figure 9.

The characteristic diffraction angles are shown below. Characteristic diffraction angles (2θ±0.2°): 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, 30.8°. The peaks are shown in the following table (Table 5).

[Table 5] Table 5 Peak position (°2θ) Strength (cts) 6.5 269.6 7.7 15.9 9.8 138.4 10.9 19.7 12.1 52.4 13.0 53.5 13.9 60.6 14.7 93.7 15.2 245.2 15.9 27.6 17.7 91.3 18.4 136.8 19.0 51.5 20.1 112.1 20.9 98.0 21.5 178.3 22.9 120.8 23.4 63.6 24.4 17.7 25.3 111.9 26.2 25.6 28.0 74.5 28.6 19.2 29.7 35.0 30.8 34.4 31.2 16.4 32.6 16.8 33.6 14.6 36.9 8.8

Thermogravimetric-differential thermal simultaneous measurement was measured according to the test conditions of TG-DTA measurement described in the above "<Reagents and measurement methods>". However, the temperature was raised at a rate of 10°C/min until 400°C. Thermogravimetric-differential thermal simultaneous measurement (TG-DTA measurement) curve: shown in Figure 10.

Comparative Example 1 Preparation of crystals of 1/2 apple acid salt of compound (I) To 1.00 g of compound (I) synthesized according to the method described in International Publication No. 2017/200087, 75 mL of 1-propanol was added, and the mixture was heated and stirred to dissolve at an internal temperature of about 75°C. 129 mg (0.55 eq.) of L-apple acid was added and rinsed with 5 mL of 1-propanol. The internal temperature was raised to 90°C, and the mixture was stirred at the same temperature for 30 minutes, then cooled to room temperature and stirred slowly. Crystals precipitated at about 70°C, and the mixture was stirred for 30 minutes while maintaining the same temperature, then cooled and stirred overnight at below 10°C, and the solid was filtered out. The mixture was dried under reduced pressure at 40°C for 2 days to obtain 1.00 g (yield 90%) of 1/2 apple acid salt. The ¹ H-NMR spectrum of the obtained 1/2 apple acid salt of compound (I) is shown below.

¹ H-NMR (DMSO - d6) δ: 8.22 (1H, s), 7.94 (1H, d, J = 8.8 Hz), 7.11 (1H, d, J = 8.8 Hz), 6.54 (1H, t, J = 5.2 Hz), 4.49 (2H, d, J = 12.8 Hz), 3.85 - 3.80 (0.5H, m), 3.37 - 3.16 (5H, m), 2.88 (2H, br s), 2.51 - 2.26 (1H, m), 1.93 - 1.72 (4H, m), 1.41 (6H, s), 1.15 (9H, s).

The powder X-ray diffraction spectrum and thermogravimetric-differential thermal analysis (TG-DTA) curve of the obtained 1/2 apple acid salt of compound (I) are shown below. Powder X-ray diffraction spectrum: shown in Figure 11.

The characteristic diffraction angles are shown below. Characteristic diffraction angles (2θ±0.2°): 6.1°, 7.1°, 10.0°, 11.2°, 17.2°, 19.6°, 16.6°, 25.2° Thermogravimetric-differential thermal analysis (TG-DTA) curve: shown in Figure 12.

Comparative Example 2 Preparation of Crystals of Acetate Salt of Compound (I) To 1.00 g of compound (I) synthesized according to the method described in International Publication No. 2017/200087, 1 mL of butyl acetate and 998 uL of acetic acid (1 molar equivalent relative to compound (I)) were added, and the mixture was stirred at room temperature to dissolve.

Heat to 50°C, add 9 mL of butyl acetate, stir for 1 hour, and solid precipitate. Stir directly and cool to room temperature, then stir in an ice bath for 1 hour and filter out the solid. Dry under reduced pressure at 40°C for 20 hours to obtain 693 mg of acetate (yield 63%). The ¹ H-NMR spectrum of the acetate of the obtained compound (I) is shown below. ¹ H-NMR (DMSO - d6) δ: 8.22 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 8.8 Hz), 6.53 (1H, t, J = 5.2 Hz), 4.48 (2H, d, J = 12.8 Hz), 3.30 - 3.13 (5H, m), 2.74 (2H, t, J = 6.7 Hz), 1.88 - 1.7 (7H, m), 1.38 (6H, s), 1.05 (9H, s).

The powder X-ray diffraction spectrum and thermogravimetric-differential thermal analysis (TG-DTA) curve of the obtained acetate salt of compound (I) are shown below. Powder X-ray diffraction spectrum: shown in Figure 13.

The characteristic diffraction angles are shown below. Characteristic diffraction angles (2θ±0.2°): 11.2°, 11.5°, 12.6°, 13.3°, 15.4°, 15.8°, 17.1°, 17.7°, 18.2°, 18.8°, 19.9°, 21.1°, 21.7°, 22.0°, 23.2°, 23.4°, 23.8°, 26.2°, 26.9°, 27.8° Thermogravimetric-differential thermal analysis (TG-DTA) curve: shown in Figure 14.

Test Example 1 Solid Stability Test The storage stability of the free form of compound (I) obtained by the method described in Examples 1, 2, and 3 was tested under the following conditions. Storage conditions: 70°C/75%RH (open system and closed system) Measurement point: 2 weeks Storage amount: about 50 mg Storage container: brown glass bottle

The powder X-ray diffraction analysis of the sample after storage was carried out according to the above method. Regarding the change of the amount of similar substances (the amount of substances detected except compound (I)), about 1 mg of the sample was weighed and dissolved in about 5 mL of a mixture of water and acetonitrile (1:1), and 5 μL of the solution was accurately measured and analyzed by HPLC according to the following method.

Column: InertSustain C18, 4.6×150 mm, 3 μm Column temperature: 40℃ Column flow rate: 1.0 mL/min Mobile phase: A; 10mM phosphate buffer (pH5.5)/acetonitrile (9:1), B; acetonitrile Detection UV (Ultraviolet): 220 nm Gradient: Time(min)        A                       B 0～20               100%→40%        0%→60% 20～27             40%                   60% 27～28             40%→100%        60%→0% 28～35             95%                   5%

As a result, the powder X-ray diffraction patterns of the free body I-type crystals, II-type crystals and III-type crystals were not observed to change, indicating that they were very stable crystals. In addition, as shown in Table 6 below, the mass of similar substances of any crystal after storage was relatively small, and no changes in appearance were observed.

[Table 6] Table 6 Total similar mass (%) Powder X-ray diffraction pattern Appearance changes Initial Value 70℃/75%RH (open system) 70℃/75%RH (closed system) Free body type I crystal 0.6% 0.5% 0.5% No significant change No significant change Soluble type II crystal 0.5% 0.6% 0.5% No significant change No significant change Soluble type III crystal 0.5% 0.8% 0.7% No significant change No significant change

Test Example 2 Dynamic moisture adsorption and desorption test VTI-SA+ (TA Instruments) was used in the test. About 10 mg of the free body type I crystal, free body type II crystal and free body type III crystal were weighed and placed in a dish. While confirming that the weight change is within 0.0100% within 5 minutes, the temperature was raised to 60°C at 1 degree per minute. In the case of weight changes, the temperature was maintained for a maximum of 5 hours before proceeding to the next step. Thereafter, the temperature was lowered to 25°C, the humidity was increased from 5%RH to 95%RH, and then reduced to 5%RH. At this time, while confirming that the weight change is within 0.00100% within 5 minutes, the humidity was applied at 5%RH each time. In the case of weight changes, the humidity was maintained for a maximum of 2 hours before proceeding to the next step.

As shown in Figures 15, 16, and 17, it can be confirmed that the hygroscopicity of the free body I-type crystals, the free body II-type crystals, and the free body III-type crystals is low. It can be seen that the free body I-type crystals and the III-type crystals show excellent low hygroscopicity.

Test Example 3 Thermal Stability Test The thermal stability test was conducted using the I-type crystals, II-type crystals, and III-type crystals of the free body obtained by the method described in Examples 1, 2, and 3. Powder X-ray diffraction measurement was performed at 25°C, and the temperature was raised to 50°C for 30 minutes, and then the powder X-ray diffraction measurement was performed. The temperature was then raised to 210°C at 10°C/10 minutes, and then the powder X-ray diffraction measurement was performed. The temperature was lowered to 25°C for 30 minutes, and then the powder X-ray diffraction measurement was performed. In the obtained spectrum, it was confirmed whether the spectrum of the subject before and after the start of the test had a new peak or a decrease.

The results of the thermal stability tests of the I-type crystals, the II-type crystals and the III-type crystals of the free body at 25°C and 210°C are shown in Figures 18, 19, 20, 21, 22 and 23 respectively.

As a result, it was confirmed that the crystal form of the I-type crystal of the free body did not change when heated to 210°C, and was relatively stable. On the other hand, it was found that the crystal form of the II-type crystal of the free body and the III-type crystal of the free body did not maintain the crystal form because new peaks appeared due to heating.

Test Example 4 Solid Stability Test According to the conditions of Test Example 1, the storage stability of the crystals of the hydrochloride salt, the crystals of the maleic acid salt, the crystals of the 1/2 apple acid salt and the crystals of the acetate salt of Compound (I) prepared by the methods described in Examples 4, 5, Comparative Example 1 and 2 was tested.

As a result, no change in the powder X-ray diffraction pattern of the crystals of the hydrochloride salt of compound (I) and the crystals of the maleic acid salt was observed, indicating that the crystals were very stable. In addition, as shown in Tables 7 and 8 below, the amount of similar substances in the crystals of the hydrochloride salt of compound (I) and the crystals of the maleic acid salt after storage was relatively small, and no change in appearance was observed.

As shown in Tables 9 and 10 below, the appearance of the crystals of the 1/2 apple acid salt and the acetate salt of Compound (I) did not change after storage, but the mass of similar substances was higher.

[Table 7] Table 7 Crystallization of hydrochloric acid salt Total similar mass (%) Powder X-ray diffraction pattern Appearance changes Initial Value 70℃/75%RH(Open system) 70℃/75%RH(closed system) 0.2% 0.2% 0.2% No significant change No significant change [Table 8] Table 8 Crystallization of maleic acid salt Total similar mass (%) Powder X-ray diffraction pattern Appearance changes Initial Value 70℃/75%RH(Open system) 70℃/75%RH(closed system) 0.1% 0.1% 0.1% No significant change No significant change [Table 9] Table 9 1/2 Crystallization of apple acid salt Total similar mass (%) Appearance changes Initial Value 70℃/75%RH(Open system) 70℃/75%RH(closed system) 0.4% 64.0% 5.2% No significant change [Table 10] Table 10 Crystallization of Acetate Total similar mass (%) Appearance changes Initial Value 70℃/75%RH(Open system) 70℃/75%RH(closed system) 0.3% 1.1% 0.3% No significant change

Test Example 5 Dynamic Moisture Adsorption and Desorption Test According to the conditions of Test Example 2, the storage stability of the crystals of the hydrochloride salt of compound (I) obtained by the method described in the above-mentioned Example 4, Example 5, Comparative Example 1, and Comparative Example 2, the crystals of the maleic acid salt, the crystals of the 1/2 apple acid salt, and the crystals of the acetate salt was tested.

The results are shown in Figures 24, 25, 26, and 27. It was confirmed that the crystals of the maleic acid salt exhibited lower hygroscopicity, and it was confirmed that the crystals of the hydrochloric acid salt exhibited lower hygroscopicity than the crystals of the 1/2 apple acid salt.

FIG1 shows the powder X-ray diffraction spectrum (CuKα) of the I-type crystal of the free form of compound (I) obtained in Example 1 (the vertical axis represents the intensity (counts), and the horizontal axis represents the diffraction angle (2θ)). FIG2 shows the thermogravimetric-differential thermal analysis (TG-DTA) curve of the I-type crystal of the free form of compound (I) obtained in Example 1. FIG3 shows the powder X-ray diffraction spectrum (CuKα) of the II-type crystal of the free form of compound (I) obtained in Example 2 (the vertical axis represents the intensity (counts), and the horizontal axis represents the diffraction angle (2θ)). FIG4 shows the thermogravimetric-differential thermal analysis (TG-DTA) curve of the II-type crystals of the free form of compound (I) obtained in Example 2. FIG5 shows the powder X-ray diffraction spectrum (CuKα) of the III-type crystals of the free form of compound (I) obtained in Example 3 (the vertical axis represents the intensity (counts), and the horizontal axis represents the diffraction angle (2θ)). FIG6 shows the thermogravimetric-differential thermal analysis (TG-DTA) curve of the III-type crystals of the free form of compound (I) obtained in Example 3. FIG. 7 shows the powder X-ray diffraction spectrum (CuKα) of the crystals of the hydrochloride of compound (I) obtained in Example 4 (the vertical axis represents the intensity (counts), and the horizontal axis represents the diffraction angle (2θ)). FIG. 8 shows the thermogravimetric-differential thermal analysis (TG-DTA) curve of the crystals of the hydrochloride of compound (I) obtained in Example 4. FIG. 9 shows the powder X-ray diffraction spectrum (CuKα) of the crystals of the maleic acid salt of compound (I) obtained in Example 5 (the vertical axis represents the intensity (counts), and the horizontal axis represents the diffraction angle (2θ)). FIG10 shows the thermogravimetric-differential thermal analysis (TG-DTA) curve of the crystals of the maleic acid salt of compound (I) obtained in Example 5. FIG11 shows the powder X-ray diffraction spectrum (CuKα) of the crystals of the 1/2 apple acid salt of compound (I) obtained in Comparative Example 1 (the vertical axis represents the intensity (counts), and the horizontal axis represents the diffraction angle (2θ)). FIG12 shows the thermogravimetric-differential thermal analysis (TG-DTA) curve of the crystals of the 1/2 apple acid salt of compound (I) obtained in Comparative Example 1. FIG. 13 shows the powder X-ray diffraction spectrum (CuKα) of the crystal of the acetate salt of compound (I) obtained in Comparative Example 2 (the vertical axis shows the intensity (counts), and the horizontal axis shows the diffraction angle (2θ)). FIG. 14 shows the thermogravimetric-differential thermal analysis (TG-DTA) curve of the crystal of the acetate salt of compound (I) obtained in Comparative Example 2. FIG. 15 shows the water adsorption-desorption isotherm of the I-type crystal of the free form of compound (I) obtained in Example 1. FIG. 16 shows the water adsorption-desorption isotherm of the II-type crystal of the free form of compound (I) obtained in Example 2. Figure 17 shows the water adsorption-desorption isotherm of the III-type crystal of the free form of compound (I) obtained in Example 3. Figure 18 shows the powder X-ray diffraction data of the I-type crystal of the free form of compound (I) obtained in Example 1 at 25°C. Figure 19 shows the powder X-ray diffraction data of the I-type crystal of the free form of compound (I) obtained in Example 1 at 210°C. Figure 20 shows the powder X-ray diffraction data of the II-type crystal of the free form of compound (I) obtained in Example 2 at 25°C. Figure 21 shows the powder X-ray diffraction data of the II-type crystal of the free form of compound (I) obtained in Example 2 at 210°C. Figure 22 shows the powder X-ray diffraction data of the III-form crystals of the free form of compound (I) obtained in Example 3 at 25°C. Figure 23 shows the powder X-ray diffraction data of the III-form crystals of the free form of compound (I) obtained in Example 3 at 210°C. Figure 24 shows the water adsorption-desorption isotherm of the crystals of the hydrochloride salt of compound (I) obtained in Example 4. Figure 25 shows the water adsorption-desorption isotherm of the crystals of the maleic acid salt of compound (I) obtained in Example 5. Figure 26 shows the water adsorption-desorption isotherm of the crystals of the 1/2 apple acid salt of compound (I) obtained in Comparative Example 1. Figure 27 shows the water adsorption-desorption isotherms of the crystals of the acetate salt of compound (I) obtained in Comparative Example 2.

Claims (32)

A type I crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in a powder X-ray diffraction spectrum (CuKα), (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5°. The I-type crystal of the free body of claim 1 has peaks at at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα), (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5°. The I-type crystal of the free body of claim 1 has peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα): 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5°. The I-type crystal of the free body of claim 1 is a crystal having a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG. 1 . The I-type crystal of the free body of claim 1 has an endothermic peak with a peak temperature of about 235° C. in simultaneous thermogravimetric-differential thermal analysis (TG-DTA analysis). A pharmaceutical composition comprising I-form crystals of the free form of any one of claims 1 to 5. A method for preparing a form I crystal of the free form of claim 1, comprising: dissolving 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one in water; The present invention further comprises a step of dissolving the compound in solvent 1, and adding solvent 2 to the obtained solution to obtain 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one. The method of claim 7, wherein solvent 1 is dimethyl sulfoxide and solvent 2 is water, or solvent 1 is tetrahydrofuran and solvent 2 is n-heptane, ethyl acetate or 2-propanol. The method of claim 7, wherein solvent 1 is dimethyl sulfoxide and solvent 2 is water. The I-type crystal of the free form of claim 1 is obtained by crystallizing 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidine-6( The 7H)-one was dissolved in dimethyl sulfoxide, and water was added to the obtained solution to obtain 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one. A type II crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in a powder X-ray diffraction spectrum (CuKα), (a) 10.4°, 22.9° and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8° and 26.5°. The II-type crystal of the free body of claim 11 has peaks at at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα), (a) 10.4°, 22.9° and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8° and 26.5°. The II-type crystal of the free body of claim 11 has peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα), 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5° and 27.9°. The form II crystal of the free body of claim 11 is a crystal having a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG3. The form II crystal of the free body of claim 11 has an endothermic peak with a peak temperature of approximately 234°C in simultaneous thermogravimetric-differential thermal analysis (TG-DTA analysis). A pharmaceutical composition comprising form II crystals of the free body of any one of claims 11 to 15. A III-form crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b) in a powder X-ray diffraction spectrum (CuKα), (a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7°. The III-type crystal of the free body of claim 17 has peaks at three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in the powder X-ray diffraction spectrum (CuKα), (a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7°. The III-type crystal of the free body of claim 17 has peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα), 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2° and 26.7°. The III-type crystal of the free body of claim 17 has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG5. The III-form crystal of the free body of claim 17 has an endothermic peak with a peak temperature of about 234° C. in simultaneous thermogravimetric-differential thermal analysis (TG-DTA analysis). A pharmaceutical composition comprising form III crystals of the free body of any one of claims 17 to 21. A crystal of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one hydrochloride, which has peaks at at least three diffraction angles selected from the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα), 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0° and 31.6°. The crystals of the hydrochloride of claim 23 have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0° and 31.6°. The crystals of the hydrochloride salt of claim 23 have a powder X-ray diffraction spectrum substantially the same as that shown in FIG. 7 . The crystals of the hydrochloride of claim 23 have an endothermic peak with a peak temperature of approximately 241° C. in thermogravimetric-differential thermal analysis (TG-DTA analysis). A pharmaceutical composition comprising crystals of the hydrochloride of any one of claims 23 to 26. A crystal of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one cis-butenedioic acid salt, which has peaks at at least three diffraction angles selected from the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα), 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7° and 30.8°. The crystals of the maleic acid salt of claim 28 have peaks at the following diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum (CuKα): 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7° and 30.8°. The crystal of maleic acid salt of claim 28 has a powder X-ray diffraction spectrum substantially the same as that shown in FIG. 9 . The crystals of the maleic acid salt of claim 28 have an endothermic peak with a peak temperature of about 245° C. in thermogravimetric-differential thermal analysis (TG-DTA analysis). A pharmaceutical composition comprising crystals of the maleic acid salt of any one of claims 28 to 31.